DIHYDRO[1,4]OXAZINO[2,3,4-hi]INDAZOLE DERIVATIVES AS 5-HYDROXYTRYPTAMINE-6 LIGANDS

ABSTRACT

The present invention provides a compound of formula I and the use thereof for the treatment of a central nervous system disorder related to or affected by the 5-HT6 receptor.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.11/786,314, filed Apr. 11, 2007, which claims the benefit of U.S.Provisional Application No. 60/791,477, filed Apr. 12, 2006, thecontents each of which are incorporated herein by reference in theirentirety.

FIELD

The present application relates to dihydro[1,4]oxazino[2,3,4-hi]indazolecompounds and their use as modulators of 5-HT6 receptor function in theenhancement of cognition and memory in human diseases such asAlzheimer's.

BACKGROUND

This application claims the benefit under 35 U.S.C. §119(e) toco-pending U.S. provisional application No. 60/791,477, filed Apr. 12,2006, which is hereby incorporated by reference in its entirety.

Serotonin (5-hydroxytryptamine) (5-HT) receptors play a critical role inmany physiological and behavioral functions in humans and animals. Thesefunctions are mediated through various 5-HT receptors distributedthroughout the body. There are now approximately fifteen different human5-HT receptor subtypes that have been cloned, many with well-definedroles in humans. One of the most recently identified 5-HT receptorsubtypes is the 5-HT6 receptor, first cloned from rat tissue in 1993(Monsma, F. J.; Shen, Y.; Ward, R. P.; Hamblin, M. W. MolecularPharmacology 1993, 43, 320-327) and subsequently from human tissue(Kohen, R.; Metcalf, M. A.; Khan, N.; Druck, T.; Huebner, K.; Sibley, D.R. Journal of Neurochemistry 1996, 66, 47-56). The receptor is aG-protein coupled receptor (GPCR) positively coupled to adenylatecyclase (Ruat, M.; Traiffort, E.; Arrang, J-M.; Tardivel-Lacombe, L.;Diaz, L.; Leurs, R.; Schwartz, J-C. Biochemical Biophysical ResearchCommunications 1993, 193, 268-276). The receptor is found almostexclusively in the central nervous system (CNS) areas both in rat and inhuman. In situ hybridization studies of the 5-HT6 receptor in rat brainusing mRNA indicate principal localization in the areas of 5-HTprojection including striatum, nucleus accumbens, olfactory tubercle,and hippocampal formation (Ward, R. P.; Hamblin, M. W.; Lachowicz, J.E.; Hoffman, B. J.; Sibley, D. R.; Dorsa, D. M. Neuroscience 1995, 64,1105-1111).

There are many potential therapeutic uses for 5-HT6 ligands in humansbased on direct effects and on indications from available scientificstudies. These studies provided information including the localizationof the receptor, the affinity of ligands with known in vivo activity,and results obtained from various animal studies conducted so far(Woolley, M. L.; Marsden, C. A.; Fone, K. C. F. Current Drug Targets:CNS & Neurological Disorders 2004, 3(1), 59-79).

One therapeutic use of modulators of 5-HT6 receptor function is in theenhancement of cognition and memory in human diseases such asAlzheimer's. The high levels of receptor found in important structuresin the forebrain, including the caudate/putamen, hippocampus, nucleusaccumbens, and cortex indicate a role for the receptor in memory andcognition since these areas are known to play a vital role in memory(Gerard, C.; Martres, M.-P.; Lefevre, K.; Miquel, M. C.; Verge, D.;Lanfumey, R.; Doucet, E.; Hamon, M.; El Mestikawy, S. Brain Research,1997, 746, 207-219). The ability of known 5-HT₆ receptor ligands toenhance cholinergic transmission also supported the cognition use(Bentley, J. C.; Boursson, A.; Boess, F. G.; Kone, F. C.; Marsden, C.A.; Petit, N.; Sleight, A. J. British Journal of Pharmacology, 1999,126(7), 1537-1542). Studies have demonstrated that a known 5-HT₆selective antagonist significantly increased glutamate and aspartatelevels in the frontal cortex without elevating levels of noradrenaline,dopamine, or 5-HT. This selective elevation of neurochemicals known tobe involved in memory and cognition indicates the role 5-HT₆ ligandsplay in cognition (Dawson, L. A.; Nguyen, H. Q.; Li, P. British Journalof Pharmacology, 2000, 130(1), 23-26). Animal studies of memory andlearning with a known selective 5-HT₆ antagonist found positive effects(Rogers, D. C.; Hatcher, P. D.; Hagan, J. J. Society of Neuroscience,Abstracts 2000, 26, 680). More recent studies have supported thisfinding in several additional animal models of cognition and memoryincluding in a novel object discrimination model (King, M. V.; Sleight,A. J.; Wooley, M. L.; Topham, I. A.; Marsden, C. A.; Fone, K. C. F.Neuropharmacology 2004, 47(2), 195-204 and Wooley, M. L.; Marsden, C.A.; Sleight, A. J.; Fone, K. C. F. Psychopharmacology, 2003, 170(4),358-367) and in a water maze model (Rogers, D. C.; Hagan, J. J.Psychopharmacology, 2001, 158(2), 114-119 and Foley, A. G.; Murphy, K.J.; Hirst, W. D.; Gallagher, H. C.; Hagan, J. J.; Upton, N.; Walsh, F.S.; Regan, C. M. Neuropsychopharmacology 2004, 29(1), 93-100).

A related therapeutic use for 5-HT₆ ligands is the treatment ofattention deficit disorders (ADD, also known as Attention DeficitHyperactivity Disorder or ADHD) in both children and adults. Because5-HT₆ antagonists enhance the activity of the nigrostriatal dopaminepathway and because ADHD has been linked to abnormalities in the caudate(Ernst, M; Zametkin, A. J.; Matochik, J. H.; Jons, P. A.; Cohen, R. M.Journal of Neuroscience 1998, 18(15), 5901-5907), 5-HT₆ antagonistsattenuate attention deficit disorders.

Early studies examining the affinity of various CNS ligands with knowntherapeutic utility or a strong structural resemblance to known drugsimplicates 5-HT₆ ligands in the treatment of schizophrenia anddepression. For example, clozapine (an effective clinical antipsychotic)has high affinity for the 5-HT₆ receptor subtype. Also, several clinicalantidepressants have high affinity for the receptor as well and act asantagonists at this site (Branchek, T. A.; Blackburn, T. P. AnnualReviews in Pharmacology and Toxicology 2000, 40, 319-334).

Further, recent in vivo studies in rats indicate that 5-HT₆ modulatorsare useful in the treatment of movement disorders including epilepsy(Stean, T.; Routledge, C.; Upton, N. British Journal of Pharmacology1999, 127 Proc. Supplement 131 P and Routledge, C.; Bromidge, S. M.;Moss, S. F.; Price, G. W.; Hirst, W.; Newman, H.; Riley, G.; Gager, T.;Stean, T.; Upton, N.; Clarke, S. E.; Brown, A. M. British Journal ofPharmacology 2000, 130(7), 1606-1612).

Therefore, it is an object of this invention to provide compounds whichare useful as therapeutic agents in the treatment of a variety ofcentral nervous system disorders related to or affected by the 5-HT6receptor.

It is another object of this invention to provide therapeutic methodsand pharmaceutical compositions useful for the treatment of centralnervous system disorders related to or affected by the 5-HT6 receptor.

It is a feature of this invention that the compounds provided may alsobe used to further study and elucidate the 5-HT6 receptor.

SUMMARY

The present invention provides a method of treating a central nervoussystem disorder relating to decreased cognition and memory in anAlzheimer's patient in need thereof, which method comprises providing tosaid patient a therapeutically effective amount of a compound of formulaI

wherein

-   -   R₁ is H, halogen, CN, NO₂, OR₇, alkyl or haloalkyl;    -   R₂ is an alkyl, cycloalkyl, aryl or heteroaryl group each group        optionally substituted or an optionally substituted 8- to        13-membered bicyclic or tricyclic ring system having a N atom at        the bridgehead and optionally containing 1, 2 or 3 additional        heteroatoms selected from N, O or S;    -   R₃ and R₄ are each independently H, or an optionally substituted        alkyl group;    -   n is an integer of 1, 2, 3, 4, or 5;    -   R₅ and R₆ are each independently H or an alkyl, alkenyl, alkynyl        or cycloalkyl, group each group optionally substituted or R₅ and        R₆ may be taken together with the atom to which they are        attached to form an optionally substituted 3- to 7-membered ring        optionally containing an additional heteroatom selected from N,        O or S; and    -   R₇ is H, alkyl or haloalkyl; or        a stereoisomer thereof or a pharmaceutically acceptable salt        thereof;        wherein the optional substituents are selected from the group        consisting of halogen atoms, nitro, cyano, thiocyanato,        hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino,        alkylamino, dialkylamino, formyl, alkoxycarbonyl, carboxyl,        alkanoyl, alkylthio, alkylsulphinyl, alkylsulphonyl, carbamoyl,        alkylamido, phenyl, phenoxy, benzyl, benzyloxy, heterocyclyl and        cycloalkyl groups.

The present invention also provides a method of enhancing cognition andmemory related to Alzheimer's disease in a patient in need thereof whichcomprises providing to said patient a therapeutically effective amountof the compound of formula I described hereinabove.

Also provided is a method of treating Alzheimer's disease in a patient,which method comprises providing to said patient a therapeuticallyeffective amount of a compound of formula I described hereinabove.

DETAILED DESCRIPTION

The 5-hydroxytryptamine-6 (5-HT6) receptor has been identified bymolecular cloning. Its ability to bind a wide range of therapeuticcompounds used in psychiatry, coupled with its intriguing distributionin the brain has stimulated significant interest in new compounds whichare capable of interacting with or affecting said receptor. Significantefforts are being made to understand the role of the 5-HT6 receptor inpsychiatry, cognitive dysfunction, motor function and control, memory,mood and the like. To that end, compounds which demonstrate a bindingaffinity for the 5-HT6 receptor are earnestly sought both as an aid inthe study of the 5-HT6 receptor and as potential therapeutic agents inthe treatment of central nervous system disorders, for example see C.Reavill and D. C. Rogers, Current Opinion in Investigational Drugs,2001, 2(1):104-109, Pharma Press Ltd and Woolley, M. L.; Marsden, C. A.;Fone, K. C. F. Current Drug Targets: CNS & Neurological Disorders 2004,3(1), 59-79.

Surprisingly, it has now been found thatdihydro[1,4]oxazino[2,3,4-hi]indazole compounds of formula I demonstrate5-HT6 affinity along with significant sub-type selectivity.Advantageously, said formula I compounds are effective therapeuticagents for the treatment of central nervous system (CNS) disordersassociated with or affected by the 5-HT6 receptor. Accordingly, thepresent invention provides a dihydro[1,4]oxazino[2,3,4-hi]indazolecompound of formula I

wherein

-   -   R₁ is H, halogen, CN, NO₂, OR₇, alkyl or haloalkyl;    -   R₂ is an alkyl, cycloalkyl, aryl or heteroaryl group each group        optionally substituted or an optionally substituted 8- to        13-membered bicyclic or tricyclic ring system having a N atom at        the bridgehead and optionally containing 1, 2 or 3 additional        heteroatoms selected from N, O or S;    -   R₃ and R₄ are each independently H, or an optionally substituted        alkyl group;    -   n is an integer of 1, 2, 3, 4, or 5;    -   R₅ and R₆ are each independently H or an alkyl, alkenyl, alkynyl        or cycloalkyl, group each group optionally substituted or R₅ and        R₆ may be taken together with the atom to which they are        attached to form an optionally substituted 3- to 7-membered ring        optionally containing an additional heteroatom selected from N,        O or S; and    -   R₇ is H, alkyl or haloalkyl; or        a stereoisomer thereof or a pharmaceutically acceptable salt        thereof.

Preferred compounds of the invention are those compounds of formula Iwherein n is 1. Another group of preferred compounds is those formula Icompounds wherein R₂ is an optionally substituted aryl or heteroarylgroup or an optionally substituted 8- to 13-membered bicyclic ortricyclic ring system having a N atom at the bridgehead and optionallycontaining 1, 2 or 3 additional heteroatoms selected from N, O or S.Also preferred are those formula I compounds wherein R₅ and R₆ are eachindependently H or alkyl or R₅ and R₆ are taken together with the atomto which they are attached to form an optionally substituted 3- to7-membered ring.

More preferred compounds of the invention are those compounds of formulaI wherein n is 1 and R₁ is H, halogen or C₁-C₃ alkyl. Another group ofmore preferred compounds is those compounds of formula I wherein n is 1;R₂ is an optionally substituted aryl or heteroaryl group; and R₃ and R₄are H. A further group of more preferred compounds are those compoundsof formula I wherein n is 1; R₂ is naphthyl; and R₅ and R₆ are eachindependently H or alkyl or R₅ and R₆ are taken together with the atomto which they are attached to form an optionally substituted 3- to5-membered ring.

Among the preferred compounds of the invention are:

-   N,N-dimethyl-1-[6-(1-naphthylsulfonyl)-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazol-2-yl]-methanamine;-   6-(1-naphthylsulfonyl)-2-(pyrrolidin-1-1    ylmethyl)-2,3-dihydro[1,4]oxazino[2,3,4-hi]-indazole;-   6-(1-naphthylsulfonyl)-2-(piperidin-1-1-1ylmethyl)-2,3-dihydro[1,4]oxazino[2,3,4-hi]-indazole;-   1-[6-(1-naphthylsulfonyl)-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazol-2-yl]-methan-amine;    a stereoisomer thereof; or a pharmaceutically acceptable salt    thereof.

An optionally substituted moiety may be substituted with one or moresubstituents. The substituent groups, which are optionally present, maybe one or more of those customarily employed in the development ofpharmaceutical compounds or the modification of such compounds toinfluence their structure/activity, persistence, absorption, stabilityor other beneficial property. Specific examples of such substituentsinclude halogen atoms, nitro, cyano, thiocyanato, cyanato, hydroxyl,alkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino,formyl, alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsuphinyl,alkylsulphonyl, carbamoyl, alkylamido, phenyl, phenoxy, benzyl,benzyloxy, heterocyclyl or cycloalkyl groups, preferably halogen atomsor lower alkyl or lower haloalkyl groups. Unless otherwise specified,typically, 1-3 substituents may be present.

The term “halogen”, as used herein, designates fluorine, chlorine,bromine, and iodine.

As used herein, the term “alkyl” includes both (C₁-C₁₀) straight chainand (C₃-C₁₂) branched-chain (unless defined otherwise) monovalentsaturated hydrocarbon moiety. Examples of saturated hydrocarbon alkylmoieties include, but are not limited to, chemical groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl,sec-butyl; higher homologs such as n-pentyl, n-hexyl, and the like.Specifically included within the definition of “alkyl” are those alkylgroups that are optionally substituted. Suitable alkyl substitutionsinclude, but are not limited to, CN, OH, halogen, phenyl, carbamoyl,carbonyl, alkoxy or aryloxy.

As used herein, the term “haloalkyl” designates a C_(n)H_(2n+1) grouphaving from one to 2n+1 halogen atoms which may be the same ordifferent. Examples of haloalkyl groups include CF₃, CH₂C₁, C₂H₃BrCl,C₃H₅F₂, or the like.

The term “alkenyl”, as used herein, refers to either a (C₂-C₈) straightchain or (C₃-C₁₀) branched-chain monovalent hydrocarbon moietycontaining at least one double bond. Such hydrocarbon alkenyl moietiesmay be mono or polyunsaturated, and may exist in the E or Zconfigurations. The compounds of this invention are meant to include allpossible E and Z configurations. Examples of mono or polyunsaturatedhydrocarbon alkenyl moieties include, but are not limited to, chemicalgroups such as vinyl, 2-propenyl, isopropenyl, crotyl, 2-isopentenyl,butadienyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), or thelike.

Similarly, the term “alkynyl”, as used herein, refers to either a(C₂-C₈) straight chain or (C₃-C₁₀) branched-chain monovalent hydrocarbonmoiety containing at least one triple bond. Such hydrocarbon alkenylmoieties may be mono or polyunsaturated, and may exist in the E or Zconfigurations. The compounds of this invention are meant to include allpossible E and Z configurations. Examples of mono or polyunsaturatedhydrocarbon alkynyl moieties include, but are not limited to, chemicalgroups such as 2-propynyl, 3-pentynyl, or the like.

The term “cycloalkyl”, as used herein, refers to a monocyclic, bicyclic,tricyclic, fused, bridged, or spiro monovalent saturated hydrocarbonmoiety of 3-10 carbon atoms. Examples of cycloalkyl moieties include,but are not limited to, chemical groups such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, adamantyl,spiro[4.5]decanyl, or the like.

The term “cycloheteroalkyl” as used herein designates a five- toseven-membered cycloalkyl ring system containing 1, 2 or 3 heteroatoms,which may be the same or different, selected from N, O or S andoptionally containing one double bond. Exemplary of the cycloheteroalkylring systems included in the term as designated herein are the followingrings wherein X is NR, O or S and R is H or an optional substituent asdefined hereinbelow.

The term “aryl”, as used herein, refers to an aromatic carbocyclicmoiety of up to 20 carbon atoms, which may be a single ring (monocyclic)or multiple rings (bicyclic, up to three rings) fused together or linkedcovalently. Examples of aryl moieties include, but are not limited to,phenyl, 1-naphthyl, 2-naphthyl, biphenyl, anthryl, phenanthryl,fluorenyl, indanyl, biphenylenyl, acenaphthenyl, acenaphthylenyl, andthe like.

The term “heteroaryl” as used herein designates an aromatic heterocyclicring system, which may be a single ring (monocyclic) or multiple rings(bicyclic, up to three rings) fused together or linked covalently.Preferably, heteroaryl is a 5- to 6-membered ring. The rings may containfrom one to four hetero atoms selected from N, O or S, wherein thenitrogen or sulfur atom is optionally oxidized, or the nitrogen atom isoptionally quarternized. Examples of heteroaryl moieties include, butare not limited to, furan, thiophene, pyrrole, pyrazole, imidazole,oxazole, isoxazole, thiazole, isothiazole, oxadiazole, triazole,pyridine, pyrimidine, pyrazine, pyridazine, benzimidazole, benzoxazole,benzisoxazole, benzothiazole, benzofuran, benzothiophene, thianthrene,dibenzofuran, dibenzothiophene, indole, indazole, quinoline,isoquinoline, quinazoline, quinoxaline, purine, or the like.

Exemplary of the 8- to 13-membered bicyclic or tricyclic ring systemshaving a N atom at the bridgehead and optionally containing 1, 2 or 3additional heteroatoms selected from N, O or S included in the term asdesignated herein are the following ring systems wherein W is NR′, O orS; and R′ is H or an optional substituent as described hereinbelow:

While shown without respect to stereochemistry, compounds of formula Iinclude all stereochemical forms of the structure; i.e., the R and Sconfigurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of the invention.The compounds of this invention may contain one or more asymmetriccenters and may thus give rise to optical isomers and diastereomers. Thepresent invention includes such optical isomers and diastereomers; aswell as the racemic and resolved, enantiomerically pure R and Sstereoisomers; as well as other mixtures of the R and S stereoisomersand pharmaceutically acceptable salts thereof. Where a stereoisomer ispreferred, it may in some embodiments be provided substantially free ofthe corresponding enantiomer. Thus, an enantiomer substantially free ofthe corresponding enantiomer refers to a compound that is isolated orseparated via separation techniques or prepared free of thecorresponding enantiomer. “Substantially free”, as used herein, meansthat the compound is made up of a significantly greater proportion ofone steriosomer, preferably less than about 50%, more preferably lessthan about 75%, and even more preferably less than about 90%.

Formula I structures depicted herein are also meant to include compoundswhich differ only in the presence of one or more isotopically enrichedatoms. For example, compounds having the present structure except forthe replacement of a hydrogen by a deuterium or tritium, or thereplacement of a carbon by a ¹³C- or ¹⁴C-enriched carbon are within thescope of this invention.

The compounds of the present invention may be converted to salts, inparticular pharmaceutically acceptable salts using art recognizedprocedures. Suitable salts with bases are, for example, metal salts,such as alkali metal or alkaline earth metal salts, for example sodium,potassium or magnesium salts, or salts with ammonia or an organic amine,such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-,di- or tri-lower alkylamine, for example ethyl-tert-butyl-, diethyl-,diisopropyl-, triethyl-, tributyl- or dimethylpropylamine, or a mono-,di-, or trihydroxy lower alkylamine, for example mono-, di- ortriethanolamine. Internal salts may furthermore be formed. The term“pharmaceutically acceptable salt”, as used herein, refers to saltsderived from organic and inorganic acids such as, for example, acetic,propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic,mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric,nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic,toluenesulfonic, camphorsulfonic, and similarly known acceptable acidswhen a compound of this invention contains a basic moiety.

Compounds of the invention include esters, carbamates or otherconventional prodrug forms, which in general, are functional derivativesof the compounds of the invention and which are readily converted to theinventive active moiety in vivo. Correspondingly, the method of theinvention embraces the treatment of the various conditions describedhereinabove with a compound of formula I or with a compound which is notspecifically disclosed but which, upon administration, converts to acompound of formula I in vivo.

Advantageously, the present invention also provides a convenient andeffective process for the preparation of a compound of formula I whichcomprises reacting a compound of formula II with an amine of formulaIII, optionally in the presence of a solvent, to give the compound offormula I. The process is shown hereinbelow in flow diagram I wherein Xis Cl, Br or I.

Solvents suitable for use in the process of the invention includedimethylsulfoxide, dimethyl formamide, dioxane, or the like, or amixture thereof.

Compounds of formula II may be prepared using conventional syntheticmethods and, if required, standard isolation or separation techniques.For example, compounds of formula II wherein n is 1 and the aminoalkylmoiety is attached in the 2-position (IIa) may be prepared by reactingan ortho-fluoronitrobenzene compound of formula IV with1,3-dichloropropan-2-ol in the presence of a base such as lithiumdiisopropylamide (LDA) to form the compound of formula V; reacting theformula V compound with a chloromethanesulfonyl compound of formula VIin the presence of a base such as potassium t-butoxide to give thecompound of formula VII; reducing the formula VII compound with aconventional reducing agent such as H₂ and a Palladium on Carboncatalyst to form the amino compound of formula VIII; cyclizing theformula VIII amine in the presence of NaNO₂ and HCl to give the indazolecompound of formula IX; and reacting the formula IX indazole withtriethylamine to give the desired dihydro-oxazinoindazole of formulaIIa. The reaction is shown in flow diagram II.

Advantageously, the formula I compounds of the invention are useful forthe treatment of CNS disorders related to or affected by the 5-HT6receptor including motor, mood, personality, behavioral, psychiatric,cognitive, neurodegenerative, or the like disorders, for exampleAlzheimer's disease, Parkinson's disease, attention deficit disorder,anxiety, epilepsy, depression, obsessive compulsive disorder, sleepdisorders, neurodegenerative disorders (such as head trauma or stroke),feeding disorders (such as anorexia or bulimia), schizophrenia, memoryloss, disorders associated withdrawal from drug or nicotine abuse, orthe like or certain gastrointestinal disorders such as irritable bowelsyndrome. Accordingly, the present invention provides a method for thetreatment of a disorder of the central nervous system related to oraffected by the 5-HT6 receptor in a patient in need thereof whichcomprises providing said patient a therapeutically effective amount of acompound of formula I as described hereinabove. The compounds may beprovided by oral or parenteral administration or in any common mannerknown to be an effective administration of a therapeutic agent to apatient in need thereof.

The term “providing” as used herein with respect to providing a compoundor substance embraced by the invention, designates either directlyadministering such a compound or substance, or administering a prodrug,derivative or analog which forms an equivalent amount of the compound orsubstance within the body.

The inventive method includes: a method for the treatment ofschizophrenia; a method for the treatment of a disease associated with adeficit in memory, cognition, and/or learning or a cognitive disordersuch as Alzheimer's disease or attention deficit disorder; a method forthe treatment of developmental disorders such as schizophrenia; Down'ssyndrome, Fragile X syndrome, autism or the like; a method for thetreatment of behavioral disorders, e.g., anxiety, depression, orobsessive compulsive disorder; a method for the treatment of motion ormotor disorders such as Parkinson's disease or epilepsy; a method forthe treatment of a neurodegenerative disorder such as stroke or headtrauma or withdrawal from drug addiction including addiction tonicotine, alcohol, or other substances of abuse, or any other CNSdisease or disorder associated with or related to the 5-HT6 receptor.

In one embodiment, the present invention provides a method for treatingattention deficit disorders (ADD, also known as Attention DeficitHyperactivity Disorder or ADHD) in both children and adults.Accordingly, in this embodiment, the present invention provides a methodfor treating attention deficit disorders in a pediatric patient.

The present invention therefore provides a method for the treatment ofeach of the conditions listed above in a patient, preferably in a human,said method comprises providing said patient a therapeutically effectiveamount of a compound of formula I as described hereinabove. Thecompounds may be provided by oral or parenteral administration or in anycommon manner known to be an effective administration of a therapeuticagent to a patient in need thereof.

The therapeutically effective amount provided in the treatment of aspecific CNS disorder may vary according to the specific condition(s)being treated, the size, age and response pattern of the patient, theseverity of the disorder, the judgment of the attending physician andthe like. In general, effective amounts for daily oral administrationmay be about 0.01 to 1,000 mg/kg, preferably about 0.5 to 500 mg/kg andeffective amounts for parenteral administration may be about 0.1 to 100mg/kg, preferably about 0.5 to 50 mg/kg.

In actual practice, the compounds of the invention are provided byadministering the compound or a precursor thereof in a solid or liquidform, either neat or in combination with one or more conventionalpharmaceutical carriers or excipients. Accordingly, the presentinvention provides a pharmaceutical composition which comprises apharmaceutically acceptable carrier and an effective amount of acompound of formula I as described hereinabove.

In one embodiment, the invention relates to compositions comprising atleast one compound of formula I, or a pharmaceutically acceptable saltthereof, and one or more pharmaceutically acceptable carriers,excipients, or diluents. Such compositions include pharmaceuticalcompositions for treating or controlling disease states or conditions ofthe central nervous system. In certain embodiments, the compositionscomprise mixtures of one or more compounds of formula I.

In certain embodiments, the invention relates to compositions comprisingat least one compound of formula I, or a pharmaceutically acceptablesalt thereof, and one or more pharmaceutically acceptable carriers,excipients, or diluents. Such compositions are prepared in accordancewith acceptable pharmaceutical procedures. Pharmaceutically acceptablecarriers are those carriers that are compatible with the otheringredients in the formulation and are biologically acceptable.

The compounds of formula I may be administered orally or parenterally,neat, or in combination with conventional pharmaceutical carriers.Applicable solid carriers can include one or more substances that canalso act as flavoring agents, lubricants, solubilizers, suspendingagents, fillers, glidants, compression aids, binders,tablet-disintegrating agents, or encapsulating materials. In powders,the carrier is a finely divided solid that is in admixture with thefinely divided active ingredient. In tablets, the active ingredient ismixed with a carrier having the necessary compression properties insuitable proportions and compacted in the shape and size desired. Thepowders and tablets preferably contain up to 99% of the activeingredient. Suitable solid carriers include, for example, calciumphosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine, low melting waxes and ion exchange resins.

In certain embodiments, a compound of formula I is provided in adisintegrating tablet formulation suitable for pediatric administration.

Liquid carriers can be used in preparing solutions, suspensions,emulsions, syrups and elixirs. The active ingredient can be dissolved orsuspended in a pharmaceutically acceptable liquid carrier such as water,an organic solvent, a mixture of both, or a pharmaceutically acceptableoil or fat. The liquid carrier can contain other suitable pharmaceuticaladditives such as, for example, solubilizers, emulsifiers, buffers,preservatives, sweeteners, flavoring agents, suspending agents,thickening agents, colors, viscosity regulators, stabilizers orosmo-regulators. Suitable examples of liquid carriers for oral andparenteral administration include water (particularly containingadditives as above, e.g. cellulose derivatives, preferably sodiumcarboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols e.g. glycols) and their derivatives,and oils (e.g. fractionated coconut oil and arachis oil). For parenteraladministration, the carrier can also be an oily ester such as ethyloleate and isopropyl myristate. Sterile liquid carriers are used insterile liquid form compositions for parenteral administration. Theliquid carrier for pressurized compositions can be halogenatedhydrocarbon or other pharmaceutically acceptable propellant.

In certain embodiments, a liquid pharmaceutical composition is providedwherein said composition is suitable for pediatric administration. Inother embodiments, the liquid composition is a syrup or suspension.

Liquid pharmaceutical compositions that are sterile solutions orsuspensions can be administered by, for example, intramuscular,intraperitoneal or subcutaneous injection. Sterile solutions can also beadministered intravenously. Compositions for oral administration can bein either liquid or solid form.

The compounds of formula I may be administered rectally or vaginally inthe form of a conventional suppository. For administration by intranasalor intrabronchial inhalation or insufflation, the compounds of formula Ican be formulated into an aqueous or partially aqueous solution, whichcan then be utilized in the form of an aerosol. The compounds of formulaI can also be administered transdermally through the use of atransdermal patch containing the active compound and a carrier that isinert to the active compound, is non-toxic to the skin, and allowsdelivery of the agent for systemic absorption into the blood stream viathe skin. The carrier can take any number of forms such as creams andointments, pastes, gels, and occlusive devices. The creams and ointmentscan be viscous liquid or semisolid emulsions of either the oil-in-wateror water-in-oil type. Pastes comprised of absorptive powders dispersedin petroleum or hydrophilic petroleum containing the active ingredientcan also be suitable. A variety of occlusive devices can be used torelease the active ingredient into the blood stream such as asemipermeable membrane covering a reservoir containing the activeingredient with or without a carrier, or a matrix containing the activeingredient. Other occlusive devices are known in the literature.

Preferably the pharmaceutical composition is in unit dosage form, e.g.as tablets, capsules, powders, solutions, suspensions, emulsions,granules, or suppositories. In such form, the composition is sub-dividedin unit dose containing appropriate quantities of the active ingredient;the unit dosage forms can be packaged compositions, for example,packeted powders, vials, ampoules, prefilled syringes or sachetscontaining liquids. The unit dosage form can be, for example, a capsuleor tablet itself, or it can be the appropriate number of any suchcompositions in package form.

The therapeutically effective amount of a compound of formula I providedto a patient will vary depending upon what is being administered, thepurpose of the administration, such as prophylaxis or therapy, the stateof the patient, the manner of administration, and the like. Intherapeutic applications, compounds of formula I are provided to apatient suffering from a condition in an amount sufficient to treat orat least partially treat the symptoms of the condition and itscomplications. An amount adequate to accomplish this is a“therapeutically effective amount” as described previously herein. Thedosage to be used in the treatment of a specific case must besubjectively determined by the attending physician. The variablesinvolved include the specific condition and the size, age, and responsepattern of the patient. The treatment of substance abuse follows thesame method of subjective drug administration under the guidance of theattending physician. Generally, a starting dose is about 5 mg per daywith gradual increase in the daily dose to about 150 mg per day, toprovide the desired dosage level in the patient.

In certain embodiments, the present invention is directed to prodrugs ofcompounds of formula I. The term “prodrug,” as used herein, means acompound that is convertible in vivo by metabolic means (e.g. byhydrolysis) to a compound of formula I. Various forms of prodrugs areknown in the art such as those discussed in, for example, Bundgaard,(ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.),Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen,et al., (ed). “Design and Application of Prodrugs, Textbook of DrugDesign and Development, Chapter 5, 113-191 (1991), Bundgaard, et al.,Journal of Drug Delivery Reviews, 8:1-38 (1992), Bundgaard, J. ofPharmaceutical Sciences, 77:285 et seq. (1988); and Higuchi and Stella(eds.) Prodrugs as Novel Drug Delivery Systems, American ChemicalSociety (1975).

For a more clear understanding, and in order to illustrate the inventionmore clearly, specific examples thereof are set forth hereinbelow. Thefollowing examples are merely illustrative and are not to be understoodas limiting the scope and underlying principles of the invention in anyway. The term HNMR designates proton nuclear magnetic resonance. Theterm MS designates mass spectrum. The terms THF, EtOAc, DMF and DMSOdesignate tetrahydrofuran, ethyl acetate, dimethyl formamide anddimethylsulfoxide, respectively. All chromatography is performed usingSiO₂ as support. Unless otherwise noted, all parts are parts by weight.

EXAMPLES Example 1 Preparation of1-(2-Chloro-1-chloromethyl-ethoxy)-2-nitro-benzene

A solution of 1,3-dichloro-propan-2-ol (1.29 g, 10 mmoles) in THF, undernitrogen, was cooled to 0° C., treated dropwise with Ilithiumdiisopropylamide (LDA) (5 ml, 2M solution in hexanes, 10 mmoles), whilemaintaining the temperature constant at 0° C., stirred at 0° C. for 15minutes, treated with 1-fluoro-2-nitro-benzene (1.2 g ml, 8.5 mmoles)and stirred at room temperature overnight. The reaction mixture wasdiluted with water and extracted with EtOAc. The extracts were combined,washed with brine, dried over Na₂SO₄, and concentrated under vacuum, toafford the title compound as an off-white solid (2.0 g, 8 mmoles),identified by HNMR analysis.

Example 2 Preparation of1-[3-(2-Chloro-1-chloromethyl-ethoxy)-2-nitro-phenylmethane-sulfonyl]-naphthalene

A mixture of 1-(2-chloro-1-chloromethyl-ethoxy)-2-nitro-benzene (2) (2.0g, 8 mmoles) and 1-chloromethane-sulfonyl-naphthalene (2.88 g, 12mmoles) in THF at −78° C., under nitrogen, was treated dropwise over a30 minute period with a solution of 1 M potassium t-butoxide (18 ml, 18mmoles). The reaction temperature was allowed to rise to −40° C. Thereaction mixture was stirred at −40° C. for 5 hours poured into cold 2NHCl and extracted with EtOAc. The extracts were combined, dried overNa₂SO₄, and concentrated under vacuum. The resultant solid residue wasrecrystallized from CH₂Cl₂/hexane to afford the title compound as anoff-white solid (2.4 g, 5.3 mmoles), identified by HNMR analysis.

Example 3 Preparation of2-(2-Chloro-1-chloromethyl-ethoxy)-6-(naphthalene-1-sulfonylmethyl)-phenylamine

A mixture of1-[3-(2-chloro-1-chloromethyl-ethoxy)-2-nitro-phenylmethanesulfonyl]-naphthalene(3) (2.4 g, 5.3 mmoles) and 10% Pd/C in a 1:1 mixture of THF andmethanol was hydrogenated on a Parr hydrogenator at 40 lb/in² for 20hours. The mixture was filtered through Celite. The filtrate was dilutedwith EtOAc, washed with water, dried over Na₂SO₄, and concentrated undervacuum to afford the title compound as an off white solid (2.02 g, 4.77mmoles), identified by HNMR analysis.

Example 4 Preparation of7-(2-Chloro-1-chloromethyl-ethoxy)-3-(naphthalene-1-sulfonyl)-1H-indazole

A mixture of2-(2-chloro-1-chloromethyl-ethoxy)-6-(naphthalene-1-sulfonylmethyl)-phenylamine(4) (2 g, 4.77 mmoles) in THF and 4M HCl (15 ml) was stirred, undernitrogen, at 3° C., treated dropwise with a solution of sodium nitrite(0.34 g, 5 mmoles) in H₂O (2 ml). The reaction mixture was poured into acold solution of saturated sodium bicarbonate and extracted with EtOAc.The extracts were combined, dried over Na₂SO₄ and concentrated undervacuum to afford the title compound as an off white solid (1.76 g, 4.05mmoles), identified by HNMR analysis.

Example 5 Preparation of7-Chloromethyl-2-(naphthalene-1-sulfonyl)-7,8-dihydro-6-oxa-1,8a-diaza-acenaphthylene

A mixture of7-(2-chloro-1-chloromethyl-ethoxy)-3-(naphthalene-1-sulfonyl)-1H-indazole(5) (1.76 g, 4.05 mmoles) and triethylamine (0.7 ml, 4.05 mmoles) in DMFwas stirred overnight at 70° C., cooled to room temperature, dilutedwith water and extracted with EtOAc. The extracts were combined, washedsequentially with water and brine, dried over Na₂SO₄ and concentratedunder vacuum to afford the title compound (1.5 g, 3.85 mmoles),identified by HNMR analysis.

Example 6 Preparation ofN,N-dimethyl-1-[6-(1-naphthylsulfonyl)-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazol-2-yl]methanamineHydrochloride

A mixture of7-chloromethyl-2-(naphthalene-1-sulfonyl)-7,8-dihydro-6-oxa-1,8a-diaza-acenaphthylene(0.075 g, 0.18 mmoles) and dimethylamine (0.56 ml, 1M solution in THF,0.56 mmoles) in DMSO was stirred under nitrogen at 10° C. for 4 hours,cooled to room temperature, diluted with water and extracted with EtOAc.The extracts were combined, washed sequentially with water and brine,dried over Na₂SO₄ and concentrated under vacuum. The resultant residuewas purified by flash chromatography using as eluent 5% CH₃OH/EtOAc. Thepurified compound was dissolved in methanol, treated with 1M HCl inether (0.2 ml, 0.2 mmoles) and evaporated to dryness to afford the titlecompound, MS: (ES) m/z 407.

Example 7 Preparation of6-(1-Naphthylsulfonyl)-2-(pyrrolidin-1-1-1ylmethyl)-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazoleHydrochloride

A mixture of7-chloromethyl-2-(naphthalene-1-sulfonyl)-7,8-dihydro-6-oxa-1,8a-diaza-acenaphthylene(0.075 g, 0.18 mmoles) and pyrrolidine (0.04 g, 0.56 mmoles) in DMSO wasstirred under nitrogen at 100° C. for 4 hours, cooled to roomtemperature, diluted with water and extracted with EtOAc. The extractswere combined, washed sequentially with water and brine, dried overNa₂SO₄ and concentrated under vacuum. The resultant residue was purifiedby flash chromatography using as eluent 5% CH₃OH/EtOAc. The purifiedcompound was dissolved in methanol, treated with 1 M HCl in ether (0.2ml, 0.2 mmoles) and evaporated to dryness to afford the title compound,MS: (ES) m/z 433.

Example 8 Preparation of6-(1-Naphthylsulfonyl)-2-(piperidin-1-1ylmethyl)-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazoleHydrochloride

A mixture of7-chloromethyl-2-(naphthalene-1-sulfonyl)-7,8-dihydro-6-oxa-1,8a-diaza-acenaphthylene(0.075 g, 0.18 mmoles) and piperidine (0.05 g, 0.56 mmoles) in DMSO wasstirred under nitrogen at 100° C. for 4 hours, cooled to roomtemperature, diluted with water and extracted with EtOAc. The extractswere combined, washed sequentially with water and brine, dried overNa₂SO₄ and concentrated under vacuum. The resultant residue was purifiedby flash chromatography using as eluent 5% CH₃OH/EtOAc. The purifiedcompound was dissolved in methanol, treated with 1 M HCl in ether (0.2ml, 0.2 mmoles) and concentrated to dryness to afford the titlecompound, MS: (ES) m/z 447.

Example 9 Comparative Evaluation of 5-HT₆ Binding Affinity of TestCompounds

The affinity of test compounds for the serotonin 5-HT₆ receptor wasevaluated in the following manner. Cultured Hela cells expressing humancloned 5-HT₆ receptors were harvested and centrifuged at low speed(1,000×g) for 10.0 minutes to remove the culture media. The harvestedcells were suspended in half volume of fresh physiological phosphatebuffered saline solution and recentrifuged at the same speed. Thisoperation was repeated. The collected cells were then homogenized in tenvolumes of 50 mM Tris.HCl (pH 7.4) and 0.5 mM EDTA. The homogenate wascentrifuged at 40,000×g for 30.0 min and the precipitate was collected.The obtained pellet was resuspended in 10 volumes of Tris.HCl buffer andrecentrifuged at the same speed. The final pellet was suspended in asmall volume of Tris.HCl buffer and the tissue protein content wasdetermined in aliquots of 10-25 μl volumes. Bovine Serum Albumin wasused as the standard in the protein determination according to themethod described in Lowry et al., J. Biol. Chem., 193: 265 (1951). Thevolume of the suspended cell membranes was adjusted to give a tissueprotein concentration of 1.0 mg/ml of suspension. The prepared membranesuspension (10 times concentrated) was aliquoted in 1.0 ml volumes andstored at −70° C. until used in subsequent binding experiments.

Binding experiments were performed in a 96 well microtiter plate format,in a total volume of 200 μl. To each well was added the followingmixture: 80.0 μl of incubation buffer made in 50 mM Tris.HCl buffer (pH7.4) containing 10.0 mM MgCl₂ and 0.5 mM EDTA and 20 μl of [³H]-LSD(S.A., 86.0 Ci/mmol, available from Amersham Life Science), 3.0 nM. Thedissociation constant, K_(D) of the [³H]LSD at the human serotonin 5-HT₆receptor was 2.9 nM, as determined by saturation binding with increasingconcentrations of [³H]LSD. The reaction was initiated by the finaladdition of 100.0 μl of tissue suspension. Nonspecific binding wasmeasured in the presence of 10.0 μM methiothepin. The test compoundswere added in 20.0 μl volume.

The reaction was allowed to proceed in the dark for 120 minutes at roomtemperature, at which time, the bound ligand-receptor complex wasfiltered off on a 96 well unifilter with a Packard Filtermate® 196Harvester. The bound complex caught on the filter disk was allowed toair dry and the radioactivity is measured in a Packard TopCount®equipped with six photomultiplier detectors, after the addition of 40.0μl Microscint®-20 scintillant to each shallow well. The unifilter platewas heat-sealed and counted in a PackardTopCount® with a tritiumefficiency of 31.0%.

Specific binding to the 5-HT₆ receptor was defined as the totalradioactivity bound less the amount bound in the presence of 10.0 μMunlabeled methiothepin. Binding in the presence of varyingconcentrations of test compound was expressed as a percentage ofspecific binding in the absence of test compound. The results wereplotted as log % bound versus log concentration of test compound.Nonlinear regression analysis of data points with a computer assistedprogram Prism® yielded both the IC₅₀ and the K_(i) values of testcompounds with 95% confidence limits. A linear regression line of datapoints was plotted, from which the IC₅₀ value is determined and theK_(i) value is determined based upon the following equation:

K _(i) =IC ₅₀/(1+L/K _(D))

where L was the concentration of the radioactive ligand used and K_(D)is the dissociation constant of the ligand for the receptor, bothexpressed in nM.

Using this assay, the following K_(i) values were determined. The dataare shown in Table I, below.

TABLE I Test Compound 5-HT₆ Binding Ki (Example No.) (Nm) 6 1.6 7 3.0 8160 Comparative 5-HT6 Binding Ki Examples (Nm) Clozapine 6.0 Loxapine41.4 Bromocriptine 23.0 Methiothepin 8.3 Mianserin 44.2 Olanzepine 19.5

1. A method of treating a central nervous system disorder relating todecreased cognition and memory in an Alzheimer's patient in needthereof, which method comprises providing to said patient atherapeutically effective amount of a compound of formula I

wherein R₁ is H, halogen, CN, NO₂, OR₇, alkyl or haloalkyl; R₂ is analkyl, cycloalkyl, aryl or heteroaryl group each group optionallysubstituted or an optionally substituted 8- to 13-membered bicyclic ortricyclic ring system having a N atom at the bridgehead and optionallycontaining 1, 2 or 3 additional heteroatoms selected from N, O or S; R₃and R₄ are each independently H, or an optionally substituted alkylgroup; n is an integer of 1, 2, 3, 4, or 5; R₅ and R₆ are eachindependently H or an alkyl, alkenyl, alkynyl or cycloalkyl, group eachgroup optionally substituted or R₅ and R₆ may be taken together with theatom to which they are attached to form an optionally substituted 3- to7-membered ring optionally containing an additional heteroatom selectedfrom N, O or S; and R₇ is H, alkyl or haloalkyl; or a stereoisomerthereof or a pharmaceutically acceptable salt thereof; wherein theoptional substituents are selected from the group consisting of halogenatoms, nitro, cyano, thiocyanato, hydroxyl, alkyl, haloalkyl, alkoxy,haloalkoxy, amino, alkylamino, dialkylamino, formyl, alkoxycarbonyl,carboxyl, alkanoyl, alkylthio, alkylsulphinyl, alkylsulphonyl,carbamoyl, alkylamido, phenyl, phenoxy, benzyl, benzyloxy, heterocyclyland cycloalkyl groups.
 2. The method according to claim 1 comprisingenhancing cognition and memory in said Alzheimer's patient.
 3. Themethod according to claim 1 wherein n is
 1. 4. The method according toclaim 3 wherein R₂ is an optionally substituted aryl or heteroaryl groupor an optionally substituted 8- to 13-membered bicyclic or tricyclicring system having a N atom at the bridgehead and optionally containing1, 2 or 3 additional heteroatoms selected from N, O or S.
 5. The methodaccording to claim 4 wherein R₅ and R₆ are each independently H or alkylor R₅ and R₆ are taken together with the atom to which they are attachedto form an optionally substituted 3- to 7-membered ring.
 6. The methodaccording to claim 3 wherein R₁ is H, halogen or C₁-C₃ alkyl.
 7. Themethod according to claim 3 wherein R₂ is an optionally substituted arylor heteroaryl group and R₃ and R₄ are H.
 8. A method of enhancingcognition and memory related to Alzheimer's disease in a patient in needthereof which comprises providing to said patient a therapeuticallyeffective amount of a compound of formula I

wherein R₁ is H, halogen, CN, NO₂, OR₇, alkyl or haloalkyl; R₂ is analkyl, cycloalkyl, aryl or heteroaryl group each group optionallysubstituted or an optionally substituted 8- to 13-membered bicyclic ortricyclic ring system having a N atom at the bridgehead and optionallycontaining 1, 2 or 3 additional heteroatoms selected from N, O or S; R₃and R₄ are each independently H, or an optionally substituted alkylgroup; n is an integer of 1, 2, 3, 4, or 5; R₅ and R₆ are eachindependently H or an alkyl, alkenyl, alkynyl or cycloalkyl, group eachgroup optionally substituted or R₅ and R₆ may be taken together with theatom to which they are attached to form an optionally substituted 3- to7-membered ring optionally containing an additional heteroatom selectedfrom N, O or S; and R₇ is H, alkyl or haloalkyl; or a stereoisomerthereof or a pharmaceutically acceptable salt thereof; wherein theoptional substituents are selected from the group consisting of halogenatoms, nitro, cyano, thiocyanato, hydroxyl, alkyl, haloalkyl, alkoxy,haloalkoxy, amino, alkylamino, dialkylamino, formyl, alkoxycarbonyl,carboxyl, alkanoyl, alkylthio, alkylsulphinyl, alkylsulphonyl,carbamoyl, alkylamido, phenyl, phenoxy, benzyl, benzyloxy, heterocyclyland cycloalkyl groups.
 9. The method according to claim 8 wherein nis
 1. 10. The method according to claim 9 wherein R₂ is an optionallysubstituted aryl or heteroaryl group or an optionally substituted 8- to13-membered bicyclic or tricyclic ring system having a N atom at thebridgehead and optionally containing 1, 2 or 3 additional heteroatomsselected from N, O or S.
 11. The method according to claim 10 wherein R₅and R₆ are each independently H or alkyl or R₅ and R₆ are taken togetherwith the atom to which they are attached to form an optionallysubstituted 3- to 7-membered ring.
 12. The method according to claim 9wherein R₁ is H, halogen or C₁-C₃ alkyl.
 13. The method according toclaim 9 wherein R₂ is an optionally substituted aryl or heteroaryl groupand R₃ and R₄ are H.
 14. A method of treating Alzheimer's disease in apatient, which method comprises providing to said patient atherapeutically effective amount of a compound of formula I

wherein R₁ is H, halogen, CN, NO₂, OR₇, alkyl or haloalkyl; R₂ is analkyl, cycloalkyl, aryl or heteroaryl group each group optionallysubstituted or an optionally substituted 8- to 13-membered bicyclic ortricyclic ring system having a N atom at the bridgehead and optionallycontaining 1, 2 or 3 additional heteroatoms selected from N, O or S; R₃and R₄ are each independently H, or an optionally substituted alkylgroup; n is an integer of 1, 2, 3, 4, or 5; R₅ and R₆ are eachindependently H or an alkyl, alkenyl, alkynyl or cycloalkyl, group eachgroup optionally substituted or R₅ and R₆ may be taken together with theatom to which they are attached to form an optionally substituted 3- to7-membered ring optionally containing an additional heteroatom selectedfrom N, O or S; and R₇ is H, alkyl or haloalkyl; or a stereoisomerthereof or a pharmaceutically acceptable salt thereof; wherein theoptional substituents are selected from the group consisting of halogenatoms, nitro, cyano, thiocyanato, hydroxyl, alkyl, haloalkyl, alkoxy,haloalkoxy, amino, alkylamino, dialkylamino, formyl, alkoxycarbonyl,carboxyl, alkanoyl, alkylthio, alkylsulphinyl, alkylsulphonyl,carbamoyl, alkylamido, phenyl, phenoxy, benzyl, benzyloxy, heterocyclyland cycloalkyl groups.
 15. The method according to claim 14 comprisingenhancing cognition and memory in said Alzheimer's patient.
 16. Themethod according to claim 14 wherein n is
 1. 17. The method according toclaim 16 wherein R₂ is an optionally substituted aryl or heteroarylgroup or an optionally substituted 8- to 13-membered bicyclic ortricyclic ring system having a N atom at the bridgehead and optionallycontaining 1, 2 or 3 additional heteroatoms selected from N, O or S. 18.The method according to claim 17 wherein R₅ and R₆ are eachindependently H or alkyl or R₅ and R₆ are taken together with the atomto which they are attached to form an optionally substituted 3- to7-membered ring.
 19. The method according to claim 16 wherein R₁ is H,halogen or C₁-C₃ alkyl.
 20. The method according to claim 16 wherein R₂is an optionally substituted aryl or heteroaryl group and R₃ and R₄ areH.